Aryl substituted 3,4-dihydroanthracene derivatives having retinoid antagonist or retinoid inverse agonist type biological activity

ABSTRACT

Disclosed herein are compounds of the formula 
                         
wherein R 1  is independently H or alkyl of 1 to 6 carbons;
     R 2  is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;   n is an integer of between 0 and 2;   o is an integer between 0 and 3;   R 3  is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;   R 4  is heteroaryl or (R 5 ) p -heteroaryl where the heteroaryl group is 5-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S, and N;   p is an integer having the values of 0–5;   R 5  is F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )CORO 8 , N(R 8 )CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8 , C 1-10  alkyl, fluoro substituted C 1-10  alkyl, C 2-10  alkenyl having 1 to 3 double bonds, C 2-10  alkynyl having 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons;   A is (CH 2 ) q  where q is 0–5, C 3-6  branched alkyl, C 3-6  cycloalkyl, C 2-6  alkenyl having 1 or 2 double bonds, or C 2-6  alkynyl having 1 or 2 triple bonds;   B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COORO 8 , CONR 9 R 10 , CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl)3;   R 7  is C 1-5  alkyl, C 3-5  cycloalkyl, or C 2-5  alkenyl;   R 8  is C 1-10  alkyl, C 1-10  (trimethylsilyl)alkyl, or C 5-10  cycloalkyl;   R 9  and R 10  are independently hydrogen, C 1-10  alkyl, C 5-10  cycloalkyl, phenyl or R 12 -phenyl;   R 11  is C 1-6  alkyl, phenyl, or R 12 -phenyl;   R 12  is C 1-6  alkyl; and   R 13  is divalent alkyl radical of 2–5 carbons.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.09/482,700, now U.S. Pat. No. 6,538,149 filed on Jan. 13, 2000, which isa divisional of application Ser. No. 09/030,350, filed on Feb. 25, 1998,now issued as U.S. Pat. No. 6,087,505, which is a divisional ofapplication Ser. No. 08/764,466 filed on Dec. 12, 1996, now issued asU.S. Pat. No. 5,728,846.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having retinoid-like,retinoid antagonist and/or retinoid inverse-agonist-like biologicalactivity. More specifically, the present invention relates to aryl orheteroaryl substituted 3,4-dihydroanthracene and aryl or heteroarylsubstituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline derivatives which bind to retinoidreceptors and have retinoid-like, retinoid antagonist or retinoidinverse agonist-like biological activity.

2. Background Art

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil^(R), diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

European Patent Application No. 0 210 929 (published on Feb. 4, 1987)describes polycyclic compounds which are said to have certainretinoid-like, or related biological activity. U.S. Pat. Nos. 4,980,369,5,006,550, 5,015,658, 5,045,551, 5,089,509, 5,134,159, 5,162,546,5,234,926, 5,248,777, 5,264,578, 5,272,156, 5,278,318, 5,324,744,5,346,895, 5,346,915, 5,348,972, 5,348,975, 5,380,877, 5,399,561 and5,407,937, (assigned to the same assignee as the present application)and patents and publications cited therein, describe or relate tochroman, thiochroman and 1,2,3,4-tetrahydroquinoline derivatives whichhave retinoid-like biological activity.

U.S. Pat. Nos. 5,130,335; 5,324,840; 5,344,959; 5,451,605; 5,455,265;5,470,999; 5,475,022; 5,475,113; 5,489,584; 5,514,825; 5,543,534;(assigned to the same assignee as the present application) and patentsand publications cited therein, describe or relate to5,6,7,8-tetrahydronaphthalene or naphthalene derivatives which haveretinoid-like biological activity.

Still further, several co-pending applications and recently issuedpatents which are assigned to the assignee of the present application,are directed to further compounds having retinoid-like activity.

Although pharmaceutical compositions containing retinoids have wellestablished utility (as is demonstrated by the foregoing citation ofpatents and publications from the voluminous literature devoted to thissubject) retinoids also cause a number of undesired side effects attherapeutic dose levels, including headache, teratogenesis,mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skinirritation, headache and hepatotoxicity. These side effects limit theacceptability and utility of retinoids for treating disease.

It is now general knowledge in the art that two main types of retinoidreceptors exist in mammals (and other organisms). The two main types orfamilies of receptors are respectively designated the RARs and RXRs.Within each type there are subtypes; in the RAR family the subtypes aredesignated RAR_(α), RAR_(β), and RAR_(γ), in RXR the subtypes are:RXR_(α), RXB_(β) and RXR_(γ). It has also been established in the artthat the distribution of the two main retinoid receptor types, and ofthe several sub-types is not uniform in the various tissues and organsof mammalian organisms. Moreover, it is generally accepted in the artthat many unwanted side effects of retinoids are mediated by one or moreof the RAR receptor subtypes. Accordingly, among compounds havingagonist-like activity at retinoid receptors, specificity or selectivityfor one of the main types or families, and even specificity orselectivity for one or more subtypes within a family of receptors, isconsidered a desirable pharmacological property. Some compounds bind toone or more RAR receptor subtypes, but do not trigger the response whichis triggered by agonists of the same receptors. A compound that binds toa biological receptor but does not trigger an agonist-like response isusually termed an antagonist. Accordingly, the “effect” of compounds onretinoid receptors may fall in the range of having no effect at all,(inactive compound, neither agonist nor antagonist), the compound mayelicit an agonist-like response on all receptor subtypes (pan-agonist),or a compound may be a partial agonist and/or partial antagonist ofcertain receptor subtypes if the compound binds to but does not activatecertain receptor subtype or subtypes but elicits an agonist-likeresponse in other receptor subtype or subtypes. A pan antagonist is acompound that binds to all known retinoid receptors but does not elicitan agonist-like response in any of the receptors.

Recently a two-state model for certain receptors, including theabove-mentioned retinoid receptors, have emerged. In this model, anequilibrium is postulated to exist between inactive receptors andspontaneously active receptors which are capable of coupling with a Gprotein in the absence of a ligand (agonist). In this model, so-called“inverse agonists” shift the equilibrium toward inactive receptors, thusbringing about an overall inhibitory effect. Neutral antagonist do noteffect the receptor equilibrium but are capable of competing for thereceptors with both agonists (ligands) and with inverse agonists.

It has been recently discovered and described in pending applicationsassigned to the same assignee as the present application that the abovementioned retinoid antagonist and/or inverse agonist-like activity of acompound is also a useful property, in that such antagonist or inverseagonist-like compounds can be utilized to block certain undesired sideeffects of retinoids, to serve as antidotes to retinoid overdose orpoisoning, and may lend themselves to other pharmaceutical applicationsas well. More particularly, regarding the published scientific andpatent literature in this field, published PCT application WO 94/14777describes certain heterocyclic carboxylic acid derivatives which bind toRAR retinoid receptors and are said in the application to be useful fortreatment of certain diseases or conditions, such as acne, psoriasis,rheumatoid arthritis and viral infections. A similar disclosure is madein the article by Yoshimura et al. J Med. Chem. 1995, 38, 3163–3173.Kaneko et al. Med. Chem Res. (1991) 1:220–225; Apfel et al. Proc. Natl.Acad. Sci. USA Vol 89 pp 7129–7133 August 1992 Cell Biology; Eckhardt etal. Toxicology Letters, 70 (1994) 299–308; Keidel et al. Molecular andCellular Biology, Vol 14, No. 1, Jan. 1994, p 287–298; and Eyrolles etal. J. Med. Chem. 1994, 37, 1508–1517 describe compounds which haveantagonist like activity at one or more of the RAR retinoid subtypes.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula 1

wherein X₁ is —C(R₁)₂—, —C(R₁)₂—C(R₁)₂—, —S—, —O—, —NR₁—, —C(R₁)₂—O—.

-   —C(R₁)₂—S—, or —C(R₁)₂—NR₁—;

R₁ is independently H or alkyl of 1 to 6 carbons;

R₂ is optional and is defined as lower alkyl of 1 to 6 carbons, F, Cl,Br, I, CF₃, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxyof 1 to 6 carbons, or alkylthio of 1 to 6 carbons;

m is an integer between 0 and 4;

n is an integer between 0 and 2;

o is an integer between 0 and 3;

R₃ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I;

R₄ is (R₅)_(p)-phenyl, (R₅)_(p)-naphthyl, or (R₅)_(p)-heteroaryl wherethe heteroaryl group is 5-membered or 6-membered and has 1 to 3heteroatoms selected from the group consisting of O, S and N;

p is an integer having the values of 0–5;

R₅ is optional and is defined as independently F, Cl, Br, I, NO₂,N(R₈)₂, N(R₈)COR₈, NR₈CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkylgroup having 1 to 10 carbons, fluoro substituted alkyl group having 1 to10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 doublebonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, ora (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groupsindependently have 1 to 6 carbons;

Y is a phenyl or naphthyl group, or heteroaryl selected from a groupconsisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or Y is —(CR₃═CR₃)_(r)—;

r is an integer between 1 and 3;

A is (CH₂)_(q) where q is 0–5, lower branched chain alkyl having 3–6carbons, cycloalkyl having 3–6 carbons, alkenyl having 2–6 carbons and 1or 2 double bonds, alkynyl having 2–6 carbons and 1 or 2 triple bonds,with the proviso that when Y is —(CR₃═C₃)_(r)— then A is (CH₂)_(q) and qis 0;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5–10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2–5 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 for the treatment of skin-related diseases, including,without limitation, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood, and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil^(R), diseases associated with the immune system, including useof the present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

Alternatively, those compounds of the invention which act as antagonistsor inverse agonists of one or more retinoid receptor subtypes are usefulto prevent certain undesired side effects of retinoids which areadministered for the treatment or prevention of certain diseases orconditions. For this purpose the retinoid antagonist and/or inverseagonist compounds of the invention may be co-administered withretinoids. The retinoid antagonist and inverse agonist compounds of thepresent invention are also useful in the treatment of acute or chronictoxicity resulting from overdose or poisoning by retinoid drugs orVitamin A.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 in admixture with a pharmaceutically acceptableexcipient, said formulation being adapted for administration to amammal, including a human being, to treat or alleviate the conditionswhich were described above as treatable by retinoids, to beco-administered with retinoids to eliminate or reduce side effects ofretinoids, or to treat retinoid or Vitamin A overdose or poisoning.

Biological Activity, Modes of Administration

Assay of Retinoid-like or Retinoid Antagonist and Inverse Agonist-likeBiological Activity

A classic measure of retinoic acid activity involves measuring theeffects of retinoic acid on ornithine decarboxylase. The original workon the correlation between retinoic acid and decrease in cellproliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196–2201. That reference discloses that ornithine decarboxylase (ODC)activity increased precedent to polyamine biosynthesis. It has beenestablished elsewhere that increases in polyamine synthesis can becorrelated or associated with cellular proliferation. Thus, if ODCactivity could be inhibited, cell hyperproliferation could be modulated.Although all cases for ODC activity increases are unknown, it is knownthat 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Research:1662–1670,1975 may be used to demonstrate inhibition of TPA induction ofODC by compounds of this invention. “IC₆₀” is that concentration of thetest compound which causes 60% inhibition in the ODC assay. By analogy,“IC₈₀”, for example, is that concentration of the test compound whichcauses 80% inhibition in the ODC assay.

Other assays described below, measure the ability of the compounds ofthe present invention to bind to, and/or activate various retinoidreceptor subtypes. When in these assays a compound binds to a givenreceptor subtype and activates the transcription of a reporter genethrough that subtype, then the compound is considered an agonist of thatreceptor subtype. Conversely, a compound is considered an antagonist ofa given receptor subtype if in the below described co-tranfection assaysthe compound does not cause significant transcriptional activation ofthe receptor regulated reporter gene, but nevertheless binds to thereceptor with a K_(d) value of less than approximately 1 micromolar. Inthe below described assays the ability of the compounds to bind toRAR_(α), RAR_(β), RAR_(γ), RXR_(α), RXR_(β) and RXR_(Γ) receptors, andthe ability or inability of the compounds to activate transcription of areporter gene through these receptor subtypes can be tested.

Specifically, a chimeric receptor transactivation assay which tests foragonist-like activity in the RAR_(α), RAR_(β), RAR_(γ), RXR_(α) receptorsubtypes, and which is based on work published by Feigner P. L. and HolmM. (1989) Focus, 11 2 is described in detail in U.S. Pat. No. 5,455,265the specification of which is hereby expressly incorporated byreference.

A holoreceptor transactivation assay and a ligand binding assay whichmeasure the antagonist/agonist like activity of the compounds of theinvention, or their ability to bind to the several retinoid receptorsubtypes, respectively, are described in published PCT Application No.WO WO93/11755 (particularly on pages 30–33 and 37–41) published on Jun.24, 1993, the specification of which is also incorporated herein byreference. A description of the holoreceptor transactivation assay isalso provided below.

Holoreceptor Transactivation Assay

CV1 cells (5,000 cells/well) were transfected with an RAR reporterplasmid MTV-TREp-LUC (50 ng) along with one of the RAR expressionvectors (10 ng) in an automated 96-well format by the calcium phosphateprocedure of Heyman et al. Cell 68, 397–406, (1992). For RXR_(α) andRXR_(γ) transactivation assays, an RXR-responsive reporter plasmidCRBPII-tk-LUC (50 ng) along with the appropriate RXR expression vectors(10 ng) was used substantially as described by Heyman et al. above, andAllegretto et al. J. Biol. Chem. 268, 26625–26633. For RXR_(β)transactivation assays, an RXR-responsive reporter plasmid CPRE-tk-LUC(50 mg) along with RXR_(β) expression vector (10 mg) was used asdescribed in above. These reporters contain DRI elements from humanCRBPII and certain DRI elements from promoter, respectively. (seeMangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp319–349, Raven Press Ltd., New York and Heyman et al., cited above) (1,8). A β-galactosidase (50 ng) expression vector was used as an internalcontrol in the transfections to normalize for variations in transfectionefficiency. The cells were transfected in triplicate for 6 hours,followed by incubation with retinoids for 36 hours, and the extractswere assayed for luciferase and β-galactosidase activities, The detailedexperimental procedure for holoreceptor transactivations has beendescribed in Heyman et al. above, and Allegretto et al. cited above. Theresults obtained in this assay are expressed in EC₅₀ numbers, as theyare also in the chimeric receptor transactivation assay. The Heyman etal. Cell 68, 397–406, Allegretto et al. J. Biol. Chem. 268, 26625–26633,and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine,pp 319–349, Raven Press Ltd., New York, are expressly incorporatedherein by reference. The results of ligand binding assay are expressedin K_(d) numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp3099–3108, expressly incorporated herein by reference.)

Table 1 shows the results of the ligand binding assay for certainexemplary compounds of the invention for the receptor subtypes in theRAR group.

TABLE 1 Ligand Binding Assay Compound K_(d) (nanomolar, nM) No. RARαRARβ TATγ 2 13 4 7 4 15 6 11 12 17 12 33

Inverse agonists are ligands that are capable of inhibiting the basalreceptor activity of unliganded receptors. Recently, retinoic acidreceptors (RARs) have been shown to be responsive to retinoid inverseagonists in regulating basal gene transcriptional activity. Moreover,the biological effects associated with retinoid inverse agonists aredistinct from those of retinoid agonists or antagonists. For example,RAR inverse agonists, but not RAR neutral antagonists, cause adose-dependent inhibition of the protein MRP-8 in cultured humankeratinocytes differentiated with serum. MRP-8 is a specific marker ofcell differentiation, which is also highly expressed in psoriaticepidermis, but is not detectable in normal human skin. Thus, retinoidinverse agonists may offer a unique way of treating diseases such aspsoriasis.

The activity of retinoid inverse agonists can be tested by the procedureof Klein et al. J. Biol. Chem. 271, 22692–22696 (1996) which isexpressly incorporated herein by reference.

In this assay, retinoid inverse agonists are able to repress the basalactivity of a RARγ-VP-16 chimeric receptor where the constituitivelyactive domain of the herpes simplex virus (HSV) VP-16 is fused to theN-terminus of RARγ. CV-1 cells are cotransfected with RARγ-VP-16, anER-RXRα chimeric receptor and an ERE-tk-Luc chimeric reporter gene toproduce a basal level of luciferase activity, as shown by Nagpal et al.EMBO J. 12, 2349–2360 (1933) expressly incorporated herein by reference.Retinoid inverse agonists are able to inhibit the basal luciferaseactivity in these cells in a dose dependent manner and IC₅₀s measured.In this assay, Compound 2 had an IC₅₀ of 1.0 nM.

Modes of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, by Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

The partial or pan retinoid antagonist and/or retinoid inverse agonistcompounds of the invention, when used to take advantage of theirantagonist and/or inverse agonist property, can be co-administered tomammals, including humans, with retinoid agonists and, by means ofpharmacological selectivity or site-specific delivery, preferentiallyprevent the undesired effects of certain retinoid agonists. Theantagonist and/or inverse agonist compounds of the invention can also beused to treat Vitamin A overdose, acute or chronic, resulting eitherfrom the excessive intake of vitamin A supplements or from the ingestionof liver of certain fish and animals that contain high levels of VitaminA. Still further, the antagonist and/or inverse agonist compounds of theinvention can also be used to treat acute or chronic toxicity caused byretinoid drugs. It has been known in the art that the toxicitiesobserved with hypervitaminosis A syndrome (headache, skin peeling, bonetoxicity, dyslipidemias) are similar or identical with toxicitiesobserved with other retinoids, suggesting a common biological cause,that is RAR activation. Because the antagonist or inverse agonistcompounds of the present invention block or diminish RAR activation,they are suitable for treating the foregoing toxicities.

Generally speaking, for therapeutic applications in mammals, theantagonist and/or inverse agonist compounds of the invention can beadmistered enterally or topically as an antidote to vitamin A, orantidote to retinoid toxicity resulting from overdose or prolongedexposure, after intake of the causative factor (vitamin A, vitamin Aprecursor, or other retinoid) has been discontinued. Alternatively, theantagonist and/or inverse agonist compounds of the invention areco-administered with retinoid drugs, in situations where the retinoidprovides a therapeutic benefit, and where the co-administered antagonistand/or inverse agonist compound alleviates or eliminates one or moreundesired side effects of the retinoid. For this type of application theantagonist and/or inverse agonist compound may be administered in asite-specific manner, for example as a topically applied cream or lotionwhile the co-administered retinoid may be given enterally. Fortherapeutic applications the antagonist compounds of the invention, likethe retinoid agonists compounds, are incorporated into pharmaceuticalcompositions, such as tablets, pills, capsules, solutions, suspensions,creams, ointments, gels, salves, lotions and the like, using suchpharmaceutically acceptable excipients and vehicles which per se arewell known in the art. For topical application, the antagonist and/orinverse agonist compounds of the invention could also be administered asa powder or spray, particularly in aerosol form. If the drug is to beadministered systemically, it may be confected as a powder, pill, tabletor the like or as a syrup or elixir suitable for oral administration.For intravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

The antagonist and/or inverse agonist compounds also, like the retinoidagonists of the invention, will be administered in a therapeuticallyeffective dose. A therapeutic concentration will be that concentrationwhich effects reduction of the particular condition, or retards itsexpansion. When co-administering the compounds of the invention to blockretinoid-induced toxicity or side effects, the antagonist and/or inverseagonist compounds of the invention are used in a prophylactic manner toprevent onset of a particular condition, such as skin irritation.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the chronic or acute retinoid toxicity or related condition beingtreated. Such concentrations can be arrived at through routineexperimentation. However, it is anticipated that a formulationcontaining between 0.01 and 1.0 milligrams of the active compound permililiter of formulation will constitute a therapeutically effectiveconcentration for total application. If administered systemically, anamount between 0.01 and 5 mg per kg per day of body weight would beexpected to effect a

GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and as applicable 3to 6 carbons for lower branch chained and cycloalkyl groups. Loweralkenyl is defined similarly having 2 to 6 carbons for normal loweralkenyl groups, and 3 to 6 carbons for branch chained and cyclo-loweralkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6carbons for normal lower alkynyl groups, and 4 to 6 carbons for branchchained lower alkynyl groups.

The term “ester” as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. It includes organic and inorganic esters. Where B of Formula1 is —COOH, this term covers the products derived from treatment of thisfunction with alcohols or thiols preferably with aliphatic alcoholshaving 1–6 carbons. Where the ester is derived from compounds where B is—CH₂OH, this term covers compounds derived from organic acids capable offorming esters including phosphorous based and sulfur based acids, orcompounds of the formula —CH₂OCOR₁₁ where R₁₁ is any substituted orunsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromaticgroup, preferably with 1–6 carbons in the aliphatic portions.

Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this applications preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula-CK where K is(—OR)₂. Here, R is lower alkyl. Also, K may be —OR₇O— where R₇ is loweralkyl of 2–5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds inthis invention having a functionality capable of forming a salt, forexample an acid functionality. A pharmaceutically acceptable salt is anysalt which retains the activity of the parent compound and is does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri-acid may also be used.

Some of the compounds of the present invention may have trans and cis (Eand Z) isomers. In addition, the compounds of the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all such isomers per se, as well asmixtures of cis and trans isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well. In the presentapplication when no specific mention is made of the configuration (cis,trans, or R or S) of a compound (or of an asymmetric carbon) then amixture of such isomers, or either one of the isomers is intended. In asimilar vein, when in the chemical structural formulas of thisapplication a straight line representing a valence bond is drawn to anasymmetric carbon, then isomers of both R and S configuration, as wellas their mixtures are intended.

The numbering system used in the naming of the compounds of the presentinvention, as well as of the intermediate compounds utilized in thesynthetic routes leading to the compounds of the invention, isillustrated below for 3,4-dihydroanthracene, benzo[1,2-g]-chrom-3-ene,benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline andfor 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone.

Generally speaking, the 3,4-dihydroanthracene compounds of the inventionare prepared in synthetic steps which usually first involve themultistep preparation of a 3,4-dihydronaphthalene derivative thatalready includes the desired R₁, R₂, R₃ and R₄ substituents and analdehyde function in the 6 or 7-position of the 3,4-dihydronaphthalenenucleus. For the preparation of benzo[1,2-g]-chrom-3-ene,benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinolinederivatives of the invention, the first (usually multi-step) procedureinvolves the preparation of a chrom-3-ene, thiochrom-3-ene or1,2-dihydroquinoline derivative which already includes the desired R₁,R₂, R₃ and R₄ substituents of the compounds of the invention, and analdehyde function in the 6 or 7-position of the chrom-3-ene,thiochrom-3-ene or 1,2-dihydroquinoline nucleus. The aldehyde is thenreacted in a Horner Emmons or Wittig, or like reaction with an aryl orheteroaryl phosphonate that carries a side chain capable of cyclizingwith the carbocyclic aromatic group of the 3,4-dihydronaphthalene,chrom-3-ene, thiochrom-3-ene or 1,2-dihydroquinoline intermediate. Thelatter cyclization reaction forms the “C” ring of the3,4-dihydroanthracene, benzo[1,2-g]-chrom-3-ene,benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinolinecompounds of the invention.

Details of the above-outlined generalized synthetic schemes are providedbelow in connection with the description of the specific embodiments andspecific examples.

The synthetic methodology employed for the synthesis of the compounds ofthe present invention may also include transformations of the groupdesignated -A-B in Formula 1. Generally speaking, these transformationsinvolve reactions well within the skill of the practicing organicchemist. In this regard the following well known and published generalprinciples and synthetic methodology are briefly described.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine(DMAP). The ester is recovered and purified by conventional means.Acetals and ketals are readily made by the method described in March,“Advanced Organic Chemistry,” 2nd Edition, McGraw-Hill Book Company, p810). Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of q in the compounds of the invention (orprecursors thereof) before affecting the coupling or linkage in a HornerEmmons or like reaction with the aldehyde on the 3,4-dihydronaphthalene,chrom-3-ene, thiochrom-3-ene or 1,2-dihydroquinoline nucleus (where suchcompounds are not available from a commercial source) aromatic orheteroaromatic carboxylic acids are subjected to homologation bysuccessive treatment under Arndt-Eistert conditions or otherhomologation procedures. Alternatively, derivatives which are notcarboxylic acids may also be homologated by appropriate procedures. Thehomologated acids can then be esterified by the general procedureoutlined in the preceding paragraph and converted into phosphonates ofphosphonium salts suitable for the Horner Emmons or Witig reaction.Compounds of the invention as set forth in Formula 1 (or precursorsthereof) where A is an alkenyl group having one or more double bonds canbe made for example, by synthetic schemes well known to the practicingorganic chemist; for example by Wittig and like reactions, or byintroduction of a double bond by elimination of halogen from analpha-halo-arylalkyl-carboxylic acid, ester or like carboxaldehyde.Compounds of the invention or precursors thereof, where the A group hasa triple (acetylenic) bond, can be made by reaction of a correspondingaromatic methyl ketone with strong base, such as lithiumdiisopropylamide, reaction with diethyl chlorophosphate and subsequentaddition of lithium diisopropylamide.

The acids and salts derived from compounds of the invention are readilyobtainable from the corresponding esters. Basic saponification with analkali metal base will provide the acid. For example, an ester of theinvention may be dissolved in a polar solvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, lithium hydroxide or potassiumhydroxide. The solution is stirred for an extended period of time,between 15 and 20 hours, cooled, acidified and the hydrolysate recoveredby conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the ester is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about −10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1–4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1–4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, “AdvancedOrganic Chemistry”, 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers. These alcohols can be converted to esters byreacting them with appropriate acids in the presence of acid catalystsor dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an allyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds of the invention, or precursors thereof, where B is H can beprepared from the corresponding halogenated aromatic or heteroaromaticcompounds, preferably where the halogen is I.

SPECIFIC EMBODIMENTS

With reference to-the symbol Y in Formula 1, the preferred compounds ofthe invention are those where Y is phenyl, naphthyl, pyridyl, thienyl orfuryl. Even more preferred are compounds where Y is phenyl. As far assubstititutions on the Y (phenyl) and Y (pyridyl) groups are concerned,compounds are preferred where the phenyl group is 1,4 para) substitutedand where the pyridine ring is 2,5 substituted. (Substitution in the 2,5positions in the “pyridine” nomenclature corresponds to substitution inthe 6-position in the “nicotinic acid” nomenclature.) In the presentlypreferred compounds of the invention there is no R₂ substituent on the Ygroup.

The A-B group of the preferred compounds is (CH₂)_(q)COOH or(CH₂)_(q)—COOR₈, where R₈ is defined as above. Even more preferably q iszero and R₈ is lower alkyl.

The aromatic carbocyclic portions (B and C rings) of the3,4-dihydroanthracene moiety, or of the benzo[1,2-g]-chrom-3-ene,benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinolinemoiety of the compounds of the invention (as applicable) are preferablysubstituted only by the —Y(R₂)_(m)-A-B group. In other words, in thepreferred compounds there is no R₂ substituent (other than hydrogen) onthe aromatic carbocyclic portion of the condensed ring system.Similarly, in the preferred compounds of the invention there is no R₃substituent (other than hydrogen).

The moiety designated X₁ in Formula 1 is preferably —C(R₁)₂— C(R₁)₂—,—C(R₁)₂—O—, —C(R₁)₂—NR₁—, and R₁ is preferably H or methyl. The—Y(R₂)_(m)-A-B group is preferably attached to the 8-position of the3,4-dihydroanthracene nucleus and to the 7-position of thebenzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline nucleus, as applicable.

Referring now to the R₄ substituent in the compounds of Formula 1,compounds are preferred where this substituent is phenyl, R₅-substitutedphenyl, pyridyl, R₅-substituted pyridyl, thienyl, or R₅-substitutedthienyl. Even more preferred are compounds where the R₄ substituent isphenyl, 4-methylphenyl, 3-pyridyl and particularly 6-methyl-3-pyridyl,2-thienyl and particularly 5-methyl-2-thienyl.

The most preferred compounds of the invention are listed below in Table2 with reference to Formula 2 or Formula 3, as applicable.

TABLE 2 Compound No. Formula X₁* R₄* R₈* 1 2 — 4-methylphenyl Et 2 2 —4-methylphenyl H 3 2 — 5-methyl(2-thienyl) Et 4 2 — 5-methyl(2-thienyl)H 5 2 — 6-methyl(3-pyridyl) Et 6 2 — 6-methyl(3-pyridyl) H 7 3 S4-methylphenyl Et 8 3 S 4-methylphenyl H 9 3 O 4-methylphenyl Et 10 3 O4-methylphenyl H 11 3 O 5-methyl(2-thienyl) Et 12 3 O5-methyl(3-thienyl) H 13 3 S 5-methyl(2-thienyl) Et 14 3 S5-methyl(2-thienyl) H

The compounds of this invention can be made by the general proceduresoutlined above under the title ““GENERAL EMBODIMENTS AND SYNTHETICMETHODOLOGY”. The following chemical pathways represent the presentlypreferred synthetic routes to certain classes of the compounds of theinvention and to certain specific exemplary compounds. However, thesynthetic chemist will readily appreciate that the conditions set outhere for these specific embodiments can be generalized to any and all ofthe compounds represented by Formula 1.

Referring now to Reaction Scheme 1 a synthetic process is describedwhereby compounds of the invention are obtained in which, with referenceto Formula 1, X₁ is —C(R₁)₂—C(R₁)₂— and the Y group is phenyl, naphthylor heteroaryl. In other words Reaction Scheme 1 describes an example ofa synthetic route for preparing compounds of the invention which are3,4-dihydroanthracene derivatives. The reaction scheme discloses thissynthetic route for the preferred examples in which the Y group iscoupled to the 8 position of the 3,4-dihydroanthracene nucleus, and the4-position bears two (geminal) methyl substituents. Nevertheless, thoseskilled in the art will readily understand that the synthetic steps ofReaction Scheme 1 can be readily modified, within the skill of the art,to yield other 3,4-dihydroanthracene compounds of the invention. Thestarting materials for the synthetic route of Reaction Scheme 1 are 6 or7-bromo (or like halogeno) substituted 1-(2H)-naphthalenones.Specifically, for the examplary synthetic route illustrated in ReactionScheme 1 the starting material is3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A).Compound A can be obtained in accordance with the chemical scientific(Johnson et al. , J. Med. Chem. 1995, 38, 4764–4767) and patent (U.S.Pat. No. 5,543,534) literature. The Johnson et al. publication and thespecification of U.S. Pat. No. 5,543,534 are expressly incorporatedherein by reference. Another example for the starting material inReaction Scheme 1 is3,4-dihydro-4,4-dimethyl-6-bromo-1(2H)-naphthalenone. The lattercompound, when subjected to the reactions disclosed in this scheme,gives rise to 3,4-dihydroanthracene compounds of the invention where theY group is coupled to the 7-position of the 3,4-dihydroanthracenenucleus. 3,4-Dihydro-4,4-dimethyl-6-bromo-1(2H)-naphthalenone can alsobe obtained in accordance with the chemical scientific (Mathur et al.Tetrahedron, 41, 1509 1516 (1985)) and patent (U.S. Pat. No. 5,543,534)literature.

In accordance with Reaction Scheme 1,3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A) isreacted with a Grignard reagent of the formula R₄—Mg—X₂, where R₄ is anaryl or heteroaryl group as defined in connection with Formula 1, and X₂is halogen, preferably bromine. The product of the Grignard (oranalogous) reaction is a tertiary alcohol (not shown in the reactionscheme) which is dehydrated by treatment with acid, to give a 1-aryl or1-heteroaryl-7-bromo-3,4-dihydronaphthalene derivative of Formula 4. Anexample for a Grignard reagent used in the synthesis of preferredcompounds of the invention is the reagent obtained from 4-bromotoluenewith magnesium. An alternative method for obtaining the 1-aryl or1-heteroaryl-7-bromo-3,4-dihydronaphthalene derivatives of Formula 4 isa reaction between an aryl or heteroaryl halide of the formula R₄—X₂ (R₄and X₂ are defined as above, X₂ is preferably Br) with Compound A in thepresence of strong base, such as n-butyl lithium. A suitable reagent forthis reaction is, for example, 2-methyl-5-bromopyridine. As stillanother alternative, Compound A is reacted with the lithium (or othersuitable metal) salt of the formula R₄—Li, (R₄ is defined as above),that can be obtained by reaction between a heteroaryl compound (such as2-methylthiophene) and n-butyl lithium.

In the next step of the reaction sequence disclosed in Reaction Scheme1, the 1-aryl or 1-heteroaryl-7-bromo-3,4-dihydronaphthalene derivativesof Formula 4 are reacted with dimethylformamide (DMF) in the presence oftertiary-butyl lithium to provide the 1-aryl or1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula 5. Thealdehyde compounds of Formula 5 can also be obtained by first convertingthe 7-bromo function of the compounds of Formula 4 into a carboxylicacid ester function or carboxylic acid, to give the 1-aryl or1-heteroaryl-3,4-dihydronaphthalene-7-carboxylic acid esters (or acids,not shown in the scheme) of Formula 6. The carboxylic acid methyl esterderivative is obtained, for example by reaction with carbon monoxide andmethanol in the presence of palladium[2]bis(triphenylphoshine) chlorideand 1,3-bis(diphenylphosphino)propane, as shown in the scheme. Thecompounds of Formula 6 are reduced with a suitable reducing agent, suchas diisobutyl aluminum hydride (DiBAl-H) to provide the 1-aryl or1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula 5.

The aldehydes of Formula 5 are subjected to a Horner Emmons typereaction, in the presence of strong base such as n-butyl lithium inhexane, with a 1-aryl or 1-heteroaryl1-diethoxyphosphoryl-3,3-dimethoxypropane derivative of Formula 7. Anexample of the phosphonate compound, which is used in the preparation ofseveral preferred compounds of the invention, is ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate. Ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate is available inaccordance with the procedure of EPO Application No. 0 210 929(published of Feb. 4, 1987, Shroot et al.) which is incorporated hereinby reference. In accordance with the Shroot et al. reference the reagentethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate is madestarting with ethyl 4-bromobenzoate that is reacted with dimetyl acetalof acryl aldehyde, the product is hydrogenated and subsequentlybrominated (with N-bromo succinimide) and thereafter reacted withtriethylphosphite.

Other examples for the phoshonates of Formula 7 are ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)pyridine-5-carboxylate, ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)pyridine-6-carboxylate, ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)thiophene-4-carboxylate, ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)thiophene-5-carboxylate, ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)furan-4-carboxylate, ethyl2-(diethoxyphosphoryl-3,3-dimethoxypropyl)furan-5-carboxylate. These andanalogous phosphonate reagents within the scope of Formula 7 can beobtained by appropriate modification of the procedure described in theShroot et al. reference.

The product of the Horner Emmons reaction between the 1-aryl or1-heteroaryl-3,4-dihydronaphthalene-7-aldehydes of Formula 5 and the1-aryl or 1-heteroaryl 1-diethoxyphosphoryl-3,3-dimethoxypropanederivative of Formula 7 is a disubstituted ethene compound of Formula 8.Those skilled in the art will readily understand that instead of aHorner Emmons reaction, a Wittig reaction can also be employed,utilizing the appropriate phosphonium derivative, to provide compoundsof Formula 8.

The disubstituted ethene compounds of Formula 8 are cyclized, forexample by heating in a neutral solvent (such as dischloromethane), inthe presence of SnCl₄ or other suitable Friedel Crafts type catalyst, toform the “C ring” of the 3,4-dihydroanthracene derivatives of theinvention, within the scope of Formula 9. The compounds of Formula 9 canbe converted into further compounds of the invention by reaction wellknown to the synthetic organic chemist, such as saponification,esterification, amide formation and homologation. These reactions werebriefly described above, and the syntheses of these further compounds ofthe invention is indicated in Reaction Scheme 1 as conversion to“HOMOLOGS AND DERIVATIVES'.

Reaction Scheme 2 discloses the synthesis of compounds of the inventionwhere with reference to Formula 1 the X₁ group is —C(R₁)₂—O—,—C(R₁)₂—S—, or —C(R₁)₂—NR₁— where the Y group is phenyl, naphthyl orheteroaryl and the R₁ group is defined as in connection with Formula 1.In other words, Reaction Scheme 2 discloses the preferred syntheticroutes to compounds of the invention which are benzo[1,2-g]-chrom-3-ene,benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinolinederivatives. As in Reaction Scheme 1 in this scheme also the descriptionis directed to a synthetic route for the preferred examples in which theY group is coupled to the 8 position of the tricyclic condensed ring. Inthese preferred examples the 2-position of the tricyclic condensed ringbears tow (geminal) methyl substituents. Nevertheless, those skilled inthe art will readily understand that the synthetic steps of ReactionScheme 2 can be readily modified, within the skill of the art, to yieldother benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline compounds of the invention.

6-Bromochroman-4-one, 6-bromothiochroman-4-one and6-bromo-1,2,3,4-tetrahydroquinoline-4-one derivatives of Formula 10serve as starting materials in the steps shown in Reaction Scheme 1.Specifically, 2,2-dimethyl-6-bromo-thiochroman-4-one can be obtainedfrom the reaction of thiophenol with 3,3-dimethylacrilic acid, followedby cyclization of the resulting adduct, as is described in detail in the“Specific Examples” section of this application.2,2-Dimethyl-6-bromochroman-4-one can be obtained in accordance with theprocedure of Buckle et al. J. Med. Chem. 1990 33, 3028, which isexpressly incorporated herein by reference.2,2-Dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline can be obtained bybromination with N-bromosuccinimide of2,2-dimethyl-1,2,3,4-tetrahydroquinoline that is available in accordancewith the chemical literature (Helv. Chim. Acta (1990) 73, 1515–1573).

In accordance with Reaction Scheme 2, the 6-bromochroman-4-one,6-bromothiochroman-4-one or 6-bromo-1,2,3,4-tetrahydroquinoline-4-onederivative of Formula 10 is reacted with a reagent of the formula R₄—X₂,where X₂ is halogen, preferably bromine, in the presence of strong base,such as tertiary-butyl lithium or normal-butyl lithium. R₄ and X₂ aredefined as in connection with Reaction Scheme 1. 4-aryl or 4-heteroaryl6-bromochrom-3-ene, 4-aryl or 4-heteroaryl 6-bromothiochrom-3-ene or4-aryl or 4-heteroaryl 6-bromo11,2,dihydroquinoline derivatives ofFormula 11 are obtained in this reaction after acid catalyzeddehydration of the tertiary alcohol intermediate that is first formed inthe reaction with R₄—X₂. A Grignard reagent of the formula R₄—Mg—X₂, orthe metal salt, particularly the lithium salt, of an aryl or heteroarylcompond of the forula R₄—Li can also be employed, to yield the 4-aryl or4-heteroaryl derivatives of Formula 11. The 4-aryl or 4-heteroaryl6-bromochrom-3-ene, 4-aryl or 4-heteroaryl 6-bromothiochrom-3-ene or4-aryl or 4-heteroaryl 6-bromo-1,2,dihydroquinoline derivatives ofFormula 11 are converted into the aryl or heteroaryl substitutedbenzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline compounds of the invention in thesame, or substantially the same sequence of reactions, as is describedin Reaction Scheme 1. This sequence of reactions is shown in ReactionScheme 2, and specific examples for their application are described inthe “Specific Examples” section. The disubstituted ethene compounds ofFormula 13 are usually not isolated in a pure form. Rather they aresubjected to a cyclization reaction without purification to provide thecompounds of Formula 14, which can be further converted into homologsand derivatives still within the scope of the invention.

Compounds of the invention where with reference to Formula 1 the X₁group is —C(R₁)₂— can be made in analogy to the synthetic steps outlinedin Reaction Scheme 1, starting with 6-bromo-indan-1-one or from anappropriately subtituted derivative. In these synthetic schemes6-bromo-indan-1-one is used in analogy to7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound A) as astarting material. 6-bromo-3,3-dimethyl-indan-1-one is availableaccordance with the chemical literature. (See Smith et al. Org. Prep.Proced. Int., 1978, 10 123–131.)

Compounds of the invention where with reference to Formula 1, X₁ is O,S, or NR₁ can be made from the compounds 5-bromo-benzofuran-3-(2H)-one,5-bromo-benzothiophene-3-(2H)-one and 5-bromo-indol-3-(2H)-one, or fromtheir appropriately substituted derivatives, substantially in accordancewith the reaction steps set forth in Reaction Scheme 1. These areavailable in accordance with the chemical literature. For5-bromo-benzofuran-3(2H)-one see Ellingboe et al. J. Med. Chem. (1992)35 p1176, and for 5-bromo-benzothiophene-3(2H)-one see Pummerel et al.Chem. Ber. 42 (1909) 2279. 5-Bromo-indol-3-(2H) one can be obtained from5-bromo-indol-2,3-dione (Patrick et al. Tet. Letts. (1984) 25 3099) byreduction with LiAlH₄, followed by oxidation with manganese dioxide(MnO₂).

Reaction Scheme 3 provides an example for the preparation of compoundsof the invention where with reference to Formula 1 Y is —(CR₃═CR₃)_(r)—and r is 2, although those skilled in the art will be able to readilymodify the steps depicted in this reaction scheme to obtain additionalcompounds of the invention where r is 1 or 3. The dimethyl acetal ofethyl 4-oxobutyrate is the starting material in accordance with thisscheme. The latter compound can be obtained in accordance with thepublication Smith et al. J. Am. Chem. Soc. 113 (6) 1991 pp 2071–2073.The dimethyl acetal of ethyl 4-oxobutyrate is brominated withN-bromosuccinimide, and the resulting dimethyl acetal of2-bromo-4-oxobutyrate is reacted with triethylphosphite to give thedimethyl acetal of ethyl 2-diethylphosphoryl-2-oxo-butyrate. Thedimethyl acetal of ethyl 2-diethylphosphoryl-2-oxo-butyrate is reactedin a Horner Emmons type reaction, in the presence of strong base such asn-butyl lithium, with an aldehyde of Formula 15. In Formula 15 R₄ and X₁are defined as in connection with Formula 1. Therefore, the aldehyde ofFormula 15 can be an aldehyde derivative of 1-aryl or 1-heteroaryl1,2,3,4-tetrahydronaphthalene or of a 4-aryl or 4-heteroarylchrom-3-ene, 4-aryl, 4-heteroaryl thiochrom-3-ene, or 4-aryl or4-heteroaryl 1,2-dihydroquinoline. More specific examples for thealdehydes which are used in this reaction scheme are the aldehydes ofFormula 5 disclosed in connection with Reaction Scheme 1, and thealdehydes of Formula 12 disclosed in connection with Reaction Scheme 2.The product of the Horner Emmons condensation reaction is a pentenoicacid derivative of Formula 16, which is cyclized in the subsequentreaction step to provide an ethyl carboxylate derivative of the aryl orheteroaryl substituted 3,4-dihydroanthracene or aryl or heteroarylsubstituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline compounds shown in Formula 17. Theethyl carboxylate function of the compounds of Formula 17 is reducedwith a suitable reducing agent, such as diisobutyl aluminum hydride(DIBAl-H), to provide the aryl or heteroaryl substituted3,4-dihydroanthracene aldehyde, aryl or heteroaryl substitutedbenzo[1,2-g]-chrom-3-ene aldehyde, benzo[1,2-g]-thiochrom-3-ene andbenzo[1,2-g]-1,2-dihydroquinoline aldehyde compounds of Formula 18. Thealdehydes of Formula 18 are then reacted in another Horner Emmonsreaction with ethyl-diethylphosphono-3-methyl 2(E)butenoate which can beobtained in acordance with the literature procedure of Corey et al J.Org. Chem. (1974) 39 p821. The product of this last Horner Emmonsreaction is the pentadienoic acid derivative of Formula 19 which iswithin the scope of the present invention. The compounds of Formula 19can be converted into further homologs and derivatives still within thescope of the invention, as described above.

Reaction Scheme 4 discloses an alternative synthetic route for preparingthe compounds of the invention where, with reference to Formula 1, the Ygroup is aryl or heteroaryl, as specifically defined in connection withthat formula. In accordance with this scheme, the aldehyde derivative ofa 1-aryl or 1-heteroaryl 1,2,3,4-tetrahydronaphthalene compound or of a4-aryl or 4-heteroaryl chrom-3-ene, 4-aryl, 4-heteroarylthiochrom-3-ene, or 4-aryl or 4-heteroaryl 1,2-dihydroquinoline compoundof Formula 15 is reacted with the Wittig reagent[2-(1,3-dioxolan-2-yl)ethyl)-triphenylphosphonium bromide in thepresence of strong base, such as n-butyl lithium. Specific examples forthe aldehydes which are used in this reaction scheme are the aldehydesof Formula 5 disclosed in connection with Reaction Scheme 1, and thealdehydes of Formula 12 disclosed in connection with Reaction Scheme 2.The Wittig reagent [2-(1,3-dioxolan-2-yl)ethyl)triphenylphosphoniumbromide is commercially available from Aldrich Chemical Company Inc. Theproduct of the Wittig reaction is a disubstituted ethene compound ofFormula 20. The aryl or heteroaryl substituent designated “Y” isintroduced into this molecule in a Heck reaction, utilizing a halogensubstituted aryl or heteroaryl compound of the formula X₂—Y-A-B where X₂is halogen, preferably bromine or iodine, A and B are defined as inconnection with Formula 1, and Y is aryl or heteroaryl as defined inFormula 1. Examples for the reagents of formula X₂—Y-A-B are ethyl4-bromobenzoate, ethyl 2-bromopyridine-5-carboxylate, ethyl2-bromopyridine-6-carboxylate, ethyl 2-bromothiophene-4-carboxylate,ethyl 2-bromothiophene-5-carboxylate, ethyl 2-bromofuran-4-carboxylate,and ethyl 2-bromofuran-5-carboxylate. The Heck reaction is well known inthe art, and is usually conducted in a basic solvent, such astriethylamine, in the presence of a phosphine catalyst (such astris(2-methylphenyl)phosphine or tri-O-tolylphosphine) and in thepresence of palladium(II)acetate catalyst. The product of the Heckreaction is a disubstituted ethene compound of Formula 21 which isthereafter ring closed under Friedel Crafts like conditions (e. g. inthe presence of SnCl₄) as in the analogous reactions described inReaction Schemes 1 and 2, to provide the compounds of Formula 22. Thecompounds of Formula 22 are within the scope of the invention, and canbe converted into further compounds of the invention by reactions wellknown in the art. This is designated symbolically in the reaction schemeby showing conversion into homologs and derivatives.

SPECIFIC EXAMPLES1-(Tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound B)

To a mixture of Mg metal (650 mg, 27 mmol) in THF (20 mL) was added4-bromotoluene (5.3 g, 31 mmol) in THF (40 mL). The mixture was stirredfor 2 hours at ambient temperature and heated to 70° C. for 30 minutes.After cooling to ambient temperature,3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A) (2.1g, 8 mmol), in THF (5 mL) was added and heated to 70° C. for 24 hours.The mixture was cooled to ambient temperature and the reaction wasquenched by addition of H₂O. The mixture was diluted withether:ethylacetate (1:1, 100 mL) and washed with saturated NH₄Cl (15mL), water (10 mL) and brine (10 mL). The organic layer was dried withMgSO₄. Solvent was removed under reduced pressure to afford the crudeproduct as an oil. The product was dissolved in THF (20 mL). To thissolution p-toleune sulfonic acid (pTSA) (35 mg) was added and themixture was refluxed for 16 hours. The mixture was cooled to ambienttemperature, diluted with ethylacetate (160 mL), washed with 10% NaHCO₃(20 mL), brine (20 mL), dried with MgSO₄ and the solvent wasremoved byevaporation. Purification by chromatography on silica gel gave the titlecompound as a white solid.

¹HNMR (CDCl₃): δ 1.33 (s, 6H), 2.34 (d, J=4.8 Hz, 2H), 2.42 (s, 3H),6.00 (t, J=4.8 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 7.20–7.30 (m, 5H), 7.34(dd, J=2.1, 8.2 Hz, 1H).

1-(Tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C)

To a cold (−78° C.), stirred solution of1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound B 1g, 3.2 mmol), in THF (17 mL) was added t-BuLi in pentane (1.7M solution,3 mL, 5.1 mmol). After 10 minutes dry dimethylformamide (DMF) (600 mg, 8mmol) was added and the dry-ice cooling was replaced with ice-waterbath. The mixture was gradually warmed to ambient temperature anddiluted with ethylacetate (150 mL), washed with water (15 mL). Theorganic layer was dried with MgSO₄ and solvent was removed under reducedpressure. The crude material was purified by silicagel chromatography toafford the title compound as a white solid.

¹HNMR (CDCl₃): δ 1.38 (s, 6H), 2.39 (d, J=4.9 Hz, 2H), 2.43 (s, 3H),6.06 (t, J=4.9 Hz, 1H), 7.20–7.30 (m, 4H), 7.50–7.60 (m, 2H), 7.76 (dd,J=1.8, 8.0 Hz, 1H), 9.87 (s, 1H).

Ethyl4-[1-(2,2-dimethoxyethyl-2–{1(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethenyl]-benzoate(Compound E)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 350 mg,0.9 mmol, available in accordance with EPO Application No. 0 210 929published on Feb. 4, 1987), in THF (9 mL), was added n-BuLi in hexane(1.6M solution, 0.7 mL, 1.1 mmol). The mixture was stirred for 1.5hours. To this solution1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde (Compound C, 200mg, 0.72 mmol), in THF (1 mL) was added and the mixture was graduallywarmed to ambient temperature (4 h). The reaction was quenched by addingwater (5 mL), and extracted with ethyl acetate (3×25 mL). The organiclayer was washed with brine (10 mL), dried with MgSO₄ and the solventwas removed by distillation. The crude material was purified bysilicagel chromatography to afford the title compound as a colorlessoil.

¹HNMR (CDCl₃): δ 1.37 (s, 6H), 1.11 (t, J=7.1 Hz, 3H), 2.35 (d, J=4.6Hz, 2H), 2.39 (s, 3H), 3.03 (d, J=5.9 Hz, 2H), 3.13 (s, 6H), 4.29 (t,J=5.9 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 5.98 (t, J=4.6 Hz, 1H), 6.73 (s,1H), 7.13 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.40(brs, 2H), 7.48 (d, J=8.3 Hz, 2H), 8.02 (d, J=8.3 Hz, 2H).

Ethyl 4-[1(tol-4yl)-3,4-dihydro-4,4-dimethyl-anthracen-8yl]-benzoate(Compound 1)

To a cold (−50° C.) solution of ethyl4-[1-(2,2-dimethoxyethyl)-2-{1(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethenyl]-benzoate(Compound E, 19 mg, 0.04 mmol), in dichloromethane (3 mL), was addedSnCl₄ (2 mg in 0.1 mL of dichloromethane). After 15 minutes the reactionwas quenched by adding water (2 mL), extracted with ether (60 mL). Theorganic layer was washed with water (5 mL), brine (5 mL), dried withMgSO₄ and the solvent was removed by distillation. The product waspurified by silicagel chromatography to afford the title compound as awhite solid.

¹HNMR (CDCl₃): δ 1.43 (t, J=7.1 Hz, 3H), 1.47 (s, 6H), 2.42 (d, J=4.9Hz, 2H), 2.45 (s, 3H), 4.41 (q, J=7.1 Hz, 2H), 6.08 (t, J=4.9 Hz, 1H),7.25 (d, J=8.0 Hz, 2H), 7.34 d, J=8.0 Hz, 2H), 7.54 (s, 1H), 7.69 (dd,J=1.9, 8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 7.87 (d, J=8.4Hz, 1H), 7.90 (brs, 1H), 8.11 (d, J=8.4 Hz, 2H).

4-[1(Tol-4-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoic acid(Compound 2)

To a degassed solution of ethyl4-[1(tol-4-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 1, 35 mg, 0.08 mmol), in THF (1.5. mL) and MeOH (1.5 mL) wasadded LiOH (1M solution in water, 0.3. mL, 0.3 mmol). The mixture wasstirred at ambient temperature for 16 hours, diluted with ether (60 mL).The mixture was acidified with 10% HCl to pH 4, the product was isolatedas an ether insoluble white solid.

¹HNMR (DMSO-D₆): δ 1.11 (s, 6H), 2.38 (s, 3H), 2.39 (d, J=4.5 Hz, 2H),6.07 (t, J=4.5 Hz, 1H), 7.25–7.33 (m, 4H), 7.51 (s, 1H), 7.84 (dd,J=1.6, 8.6 Hz, 1H), 7.90–8.05 (m, 6H), 8.15 (s, 1H).

1-(5-Methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene(Compound F)

To a cold (−78° C.) solution of 2-methylthiophene (800 mg, 8.1 mmol) inTHF (10 mL) was added n-BuLi (1.6M solution in hexane, 5 mL). Themixture was stirred for 1.5 hours and transferred to a cold (−78° C.)flask containing 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone(Compound A, 1.63 g, 6.5 mmol), in THF (15 mL). The mixture wasgradually warmed to 0° C. The reaction mixture was diluted withether:ethylacetate (1:1, 80 mL), washed with water (10 mL), brine (10mL). dried with MgSO₄ and the solvent was removed by evaporation. Thecrude material was dissolved in dichloroethane (20 mL) and pTSA (40 mg)was added. The mixture was stirred at ambient temperature for 16 hoursand at 50° C. for 4 hours. . The reaction mixture was diluted with ether(150 mL), washed with aqueous 10% NaHCO₃ (10 mL), brine (10 mL) anddried with MgSO₄. Purification by chromatography on silica gel gave 1.35g of the title compound as a white solid.

¹HNMR (CDCl₃): δ 1.26 (s, 6H), 2.31 (d, J=4.9 Hz, 2H), 2.52 (s, 3H),6.15 (t, J=4.9 Hz, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H),7.21 (d, J=8.3H, 1H), 7.34 (dd, J=2.0, 8.3 Hz, 1H), 7.55 (d, J=2.0 Hz,1H).

1(5-Methyl-thien-2-yl)3,4-dihydro-4,4-diethyl-7-naphthaldehyde (CompoundG)

To a cold (−78° C.) solution of1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene(Compound F, 1.35 g, 4.1 mmol), in THF (20 mL) was added t-BuLi inpentane (1.7M solution, 3.5 mL, 5.95 mmol). The reaction was stirred for15 minutes. and DMF (600 mg, 5.8 mmol) was added and dry-ice cooling wasreplaced with ice-water bath. The mixture was stirred at ambienttemperature for 4 hours. The reaction mixture was diluted with ether (70mL) and washed with water (5 mL), brine (5 mL) and dried with MgSO₄.Solvent was removed by distillation. The product was purified bysilicagel chromatography to afford the title compound as a colorlessoil.

¹HNMR (CDCl₃): δ 1.35 (s, 6H), 2.35 (d, J=4.8 Hz, 2H), 2.52 (s, 3H),6.20 (t, J=4.8 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H),7.52 (d, J=7.9 Hz, 1H), 7.77 (dd, J=1.8, 7.9 Hz, 1H), 7.94 (d, J=1.8 Hz,1H), 9.93 (s, 1H).

Ethyl4-[1(2,2-dimethoxyethyl)-2-{1-(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethen-1-yl]-benzoate(Compound H)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g,3.6 mmol), in THF (20 mL) was added n-BuLi (1.6 M solution in hexane,2.5 ml, 4 mmol). The mixture was stirred for 20 minutes at −78° C. and10 min. at −10° C. The reaction mixture was recooled to −78° C. and1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-7-naphthaldehyde(Compound G, 650 mg, 2.3 mmol) in THF (4 mL) was added to it. Themixture was stirred for 2 hours at −10° C. and diluted with ether (100mL), washed with brine (10 mL) dried with MgSO₄ and the solvent wasremoved by distillation to to afford a cis and trans (E and Z) isomericmixture. Purification by chromatography on silica gel of the crudematerial afforded the title compound as an oil (^(˜)90% purity).

¹HNMR (CDCl₃): δ 1.33 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 2,32 (d, J=4.9Hz, 2H), 2.49 (s, 3H), 3.06 (d, J=5.7 Hz, 2H), 3.16 (s, 6H), 4.32 (t,J=5.7 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 6.13 (t, J=4.9 Hz, 1H), 6.70 (d,J=3.5 Hz, 1H), 6.78 (s, 1H), 6.85 (d, J=3.5 Hz, 1H), 7.37 (d, J=8.0 Hz,1H), 7.43 (dd, J=1.7, 8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 3H), 8.02 (d,J=8.3 Hz, 2H).

Ethyl4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 3)

To a cold (−50° C.) solution of ethyl4-[1-(2,2-dimethoxyethyl)-2-{1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethenyl]-benzoate(Compound H, 130 mg, 0.25 mmol), in dichloromethane (5 mL) was addedSnCl₄ (22 mg, in 0.1 mL dichloromethane). After 15 min. the reaction wasquenched by adding solid NaHCO₃ (100 mg) followed by aqueous 10% NaHCO₃(5 mL), and the resulting mixture was extracted with ether (60 mL). Theorganic layer was washed with water (5 mL), brine (5 mL) dried withMgSO₄ and the solvent was removed by distillation. The product waspurified by silicagel chromatography to afford the title compound as awhite solid.

¹HNMR (CDCl₃): δ 1.43 (t, J=7.1 Hz, 3H), 1.44 (s, 6H), 2.40 (d, J=4.8Hz, 2H), 2.56 (s, 3H), 4.41 (q, J=7.1 Hz, 2H), 6.25 (t, J=4.8 Hz, 1H),6.77 (d, J=3.4 Hz, 1H), 6.96 (d, J=3.4 Hz, 1H), 7.71 (dd, J=1.7, 8.4 Hz,1H), 7.76 (d, J=8.5 Hz, 2H), 7.78 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.95(brs, 1), 7.99 (brs, 1H), 8.12 (d, J=8.4 Hz, 2H).

4-[1(5-Methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoicacid (Compound 4)

To a stirred solution of ethyl4-[1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 3, 33 mg, 0.07 mmol), in THF (2 mL), MeOH (2 mL), was addedaqueous LiOH (1M solution, 0.2 mL, 0.2 mmol). After 16 hours, water (2mL) was added to the reaction mixture, about 50% of the organic solventswere removed by distillation, and the mixture was further diluted themixture with water (5 mL). The reaction mixture was washed with ether(10 mL) and the aqueous layer was acidified to pH 4 and extracted withethyl acetate (3×20 m). The combined organic layers were washed water (5mL), brine (10 mL), dried with MgSO₄ and the solvent was removed bydistillation. The product was recrystallized from acetone to obtain thetitle compound as a white solid.

¹HNMR (CDCl₃): δ 1.44 (s, 6H), 2.40 (d, J=4.9 Hz, 2H), 2.56 (s, 3H),6.24 (t, J=4.9 Hz, 1H), 6.79 (d, J=3.4 Hz, 1H), 6.96 (d, J=3.4 Hz, 1H),7.23 (dd, J=1.7, 8.4 Hz, 1H), 7.79 (brs, 1H), 7.80 (d, J=8.4 Hz, 2H),7.88 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 8.01 (s, 1H), 8.18 (d, J=8.4 Hz,2H).

1-(6-Methyl-pyrid-3-yl)-3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene(Compound I)

To a cold (−78° C.) solution of 6-methyl-3-bromopyridine (890 mg, 5.2mmol) in THF (15 mL) was added n-BuLi in hexane (1.6M solution, 3.5 mL,5.6 mmol) and stirred for 1 hour. This mixture was added to a flaskcontaining 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone(Compound A, 1.35 g, 5.4 mmol), in THF (5 mL) at −78° C. The reactionmixture was gradually warmed to ambient temperature and stirred for 16hours. Thereafter it was diluted with ethyl acetate (100 mL), washedwith water (10 mL), brine (10 mL) and dried with MgSO₄. Solvent wasremoved by distillation, the crude material was dissolved in toluene (25mL) and pTSA (530 mg, 2.8 mmol) was added. The mixture was heated at 90°C. for 36 hours. Thereafter it was diluted with ethyl acetate (100 mL),washed with 10% NaHCO₃ (2×10 mL), brine (10 mL), dried with MgSO₄ andthe solvent was removed by evaporation. The title compound was obtainedby recrystallization from ethyl acetate and hexane mixture (1:9).

¹HNMR (CDCl₃): δ 1.31 (s, 6H), 2.34 (d, J=4.7 Hz, 2H), 2.60 (s, 3H),6.02 (t, J=4.7 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H),7.21 (d, J=8.3 Hz, 1H), 7.34 (dd, J=2.1, 8.2 Hz, 1H), 7.51 (d, J=2.3,8.3 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H).

Ethyl1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-naphthoate(Compound J)

Carbon monoxide gas was bubbled for 5 minutes through a mixture of1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene(Compound J, 250 mg, 0.75 mmol), Et₃N (5 mL), MeOH (10 mL), DMSO (10mL), Pd(PPh₃)₂Cl₂ (70 mg, 0.1 mmol) and 1,3-bis(diphenylphophino)propane(206 mg, 0.5 mmol). The mixture was heated to 50° C. for 16 hours undera carbon monoxide atmosphere (carbon monoxide balloon). Thereaftersolvent was distilled off, water (15 mL) was added, and the mixture wasextracted with ethyl acetate (3×40 mL). The combined organic layers werewashed with water (10 mL), brine (10 mL) dried with MgSO₄ and thesolvent was removed by evaporation. The crude material was purified bysilicagel column chromatography to afford the title compound as a whitesolid.

¹HNMR (CDCl₃): δ 1.33 (s, 6H), 2.35 (d, J=4.9 Hz, 2H), 2.59 (s, 3H),3.80 (s, 3H), 6.03 (t, J=4.9 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.41 (d,J=8.0 Hz, 1H), 7.51 (dd, J=2.2, 8.0 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H),7.89 (dd, J=1.8, 8.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H).

16(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-naphthaldehyde (CompoundK)

To a cold (−78° C.) solution of methyl1-(6-methyl-pyrid-3-yl)3,4-dihydro-4,4-dimethyl-7-naphthoate (CompoundJ, 200 mg, 0.65 mmol), in dichloromethane (4 mL) was added DiBAl-H indichloromethane (1M solution, 2 mL, 2 mmol). The mixture was stirred for2 hours, quenched with aq. KOH solution (100 mg in 2 mL), and a gelprecipitate formed. The mixture was transferred to a seperatory funnel,and was extracted with ethyl acetate (3×30 mL). The combined organiclayers were washed with brine (10 mL), dried with MgSO₄, and the solventwas removed by evaporation. The crude product was dissolved indichloromethane (10 mL), MnO₂ (650 mg, 7.5 mmol) was added and themixture was stirred for 6 hours. The solid was filtered off, and thesolvent was removed to afford the title compound as a white solid.

¹HNMR (CDCl₃): δ 1.38 (s, 6H), 2.41 (d, J=4.7 Hz, 2H), 2.63 (s, 3H),6.09 (t, J=4.7 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H),7.51–7.59 (m, 3H), 7.77 (dd, J=1.8, 8.0 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H),9.86 (s, 1H).

Ethyl4-[1-(6-methyl-pyrid-3-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 5)

This compound is prepared in accordance with the procedure described forthe preparation of ethyl4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 3), from1(2-methyl-pyrid-5-yl)3,4-dihydro-4,4-dimethyl-naphthaldehyde (CompoundK) by reaction with ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D) andproceeding through the intermediate ethyl4-[1-(2,2-dimethoxyethyl)-2-{1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethen-1-yl]-benzoatewhich is cyclized by treatment with SnCl₄ in dichloromethane to give thetitle compoud.

4-[1(6-methyl-pyrid-5-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoicacid (Compound 6)

The title compound is obtained by saponification with LiOH of ethyl4-[1(tol-4-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate(Compound 5) in accordance with the procedure described for thepreparation of4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoicacid (Compound 4).

3-Methyl-3-(4-bromo-thiophenyl) butyric acid (Compound L)

A mixture of 4-bromothiophenol (9.5 g, 50 mmol), 3,3-dimethylacrylicacid (5 g, 50 mmol) and piperidine were heated (110° C.) in a screw capheavy walled tube covered with teflon cap. The reaction mixture became athick liquid after 30 minutes of heating. Heating was continued for 23hours. Then the mixture was cooled to ambient temperature, andsolved inethyl acetate (200 mL). The mixture was washed with 10% aq. HCl, water(50 mL), brine (50 mL) and dried with MgSO₄. Solvent was removed and thecrude product was recrystallized from hexane to afford the titlecompound as a colorless solid.

¹HNMR (CDCl₃): δ 1.42 (s, 6H), 2.55 (s, 2H), 7.43 (d, J=8.6 Hz, 2H),7.49 (d, J=8.6 Hz, 2H).

2,2-Dimethyl-6-bromo-thiochroman-4-one (Compound M)

To a solution of 3-methyl-3-(4-bromo-thiophenyl) butyric acid (CompoundL, 9.1 g, 33.4 mmol) in benzene (125 mL) was added oxalyl chloride (7.4g, 59 mmol). The mixture was stirred for 5 hours at ambient temperature,and thereafter washed with ice-cold 5% NaOH (100 mL), ice-cold water(2×50 mL) and brine (50 mL). The organic layer was dried with MgSO₄ andthe solvent was removed by distillation. The residual colorless oil wasdissolved in dichloromethane (50 mL), cooled to 0° C. and SnCl₄ (14.7 g,57 mmol) was added. The mixture was stirred at ambient temperature for14 hours, and poured into ice. The mixture was extracted with ethylacetate, washed with 10% NaOH, water, brine, dried with MgSO₄ and thesolvent was removed by distillation. The crude material was purified bysilicagel chromatography and after standing at ambient temperature forovernight crystalline product was collected by filtration.

¹HNMR (CDCl₃): δ 1.46 (s, 6H), 2.87 (s, 2H), 7.12 (d, J=8.4 Hz, 2H),7.50 (dd, J=2.2, 8.4 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H).

2,2-Dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N)

To a cold (−78° C.) solution of 4-bromotoluene (720 mg, 4.2 mmol) in THF(8 mL) was added t-BuLi in pentane (1.7M, 0.5 mL, 0.85 mmol). Themixture was warmed to ambient temperature over 30 minutes with stirring.This mixture was added to a flask containing2,2-dimethyl-6-bromo-thiochroman-4-one (Compound M, 140 mg, 0.4 mmol)and THF (2 mL). and stirred for 16 hours at ambient temperature. Thereaction was quenched by adding aq. NH₄Cl, and the resulting mixture wasextracted with ethylacetate, washed with brine, dried and the solventwas removed by evaporation. The product was isolated by chromatographyon silica gel. The material was dissolved in dichloromethane (5 mL) andpTSA (5 mg) was added and heated to 50° C. for 3 hours. The misture wasdiluted with ethylacetate (20 mL), washed with 10% NaHCO₃ (5 mL), brine(5 mL), dried with MgSO₄ and the solvent was removed by evaporation toafford the title compound as an oil.

¹HNMR (CDCl₃): δ 1.46 (s, 6H), 2.40 (s, 3H), 5.84 (s, 1H), 7.12–7.29 (m,7H).

2,2-Dimethyl-4(tol-4-yl)-thiochrom-3-en-6-al (Compound O)

To a cold (−78° C.) solution of2,2-dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N, 280 mg,0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution,0.66 mL). The mixture was gradually warmed to −10° C. over 25 min. andrecooled to −78° C. To this solution was added DMF (80 mg, 1.1 mmol) andstirred at ambient temperature for 5 hours. The reaction was quenched byadding water (10 mL), ethyl acetate (100 mL), and the organic layer waswashed with brine (10 mL), dried and the solvent removed bydistillation. The crude material was used in the next reaction withoutfurther purification.

Ethyl 4-[2,2-dimethyl-4-(tol-4-yl)-6,7-benzothiochrom-3-en-7-yl]benzoate(Compound 7)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 536 mg,1.4 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution, 1.2mL) and stirred for 1 hour between −78° C. and −10° C. The mixture wascooled to −78° C. and 2,2-dimethyl-4(tol-4-yl)-thiochrom-3-en-6-al(Compound O, as obtained in the previously described reaction) in THF (1mL) was added to it. The reaction mixture was stirred at ambienttemperature for 1 hour and diluted with ethyl acetate (60 mL), washedwith brine (10 mL), dried and the solvent was removed by evaporation.The crude material was purified by column chromatography to afford the Eand Z isomers as a mixture. The mixture of E and Z isomers was dissolvedin dichloromethane (4 mL) and cooled to −78° C. To the cold solution wasadded SnCl4 (110 mg, 0.42 mmol) in dichloromethane (1 mL). The reactionmixture was stirred between −78° C. and −30° C. for 30 minutes and thenquenched with ethanol (0.2 mL), diluted with ethyl acetate (30 mL),washed with brine, dried and the solvent was removed by distillation.The crude material was purified by column chromatography to obtain thetitle compound as a white solid.

¹HNMR (CDCl₃): d 1.43 (t, J=7.2 Hz, 3H), 1.53 (s, 6H), 2.44 (s, 3H),4.41 (q, J=7.2 Hz, 2H), 6.02 (s, 1H), 7.21–7.31 (m, 4H), 7.59 (s, 1H),7.69–7.75 (m, 3H), 7.80 (d, J=8.5 Hz, 1H), 7.88 (s, 2H), 8.11 (d, J=8.3HZ, 2H).

4-[2,2-dimethyl-4-(tol-4-yl)-6,7-benzothiochrom-3-en-7-yl]benzoic acid(Compound 8)

To an argon purged solution of ethyl4-[2,2-dimethyl-4-(tol-4-yl)-6,7-benzothiochrom-3-en-7-yl]benzoate(Compound 7, 12 mg, 0.03 mmol), THF (2 mL) and MeOH (1 mL) was addedLiOH in water (1M solution, 0.2 mL) and purged (with argon) for 2minutes. The mixture was stirred for 16 hours at ambeint temperature.The reaction mixture was acidified with 10% hydrochloric acid to pH 4,extracted with ethyl acetate (35 mL), washed with brine, dried and thesolvent was removed by distillation. The title compound was obtained asan off white solid.

¹HNMR (Acetone-D6): d 1.50 (s, 6H), 2.39 (s, 3H), 6.08 (s, 1H), 7.26 (s,4H), 7.84–7.96 (m , 5H), 8.12 (d, J=8.3 Hz, 3H).

2,2-Dimethyl-4(tol-4-yl)-6-bromo-chrom-3-ene (Compound P)

To cold (−78° C.) solution of 4-bromotoluene (1.71 g, 10 mmol) in THF(16 mL) was added t-BuLi in pentane (1.7M, 3 mL). The mixture was warmedto ambient temperature and stirred for 15 minutes and then recooled to−78° C. To this solution, 2,2-dimethyl-6-bromo-chroman-4-one (750 mg, 3mmol) in THF (4 mL) was added and stirred for 30 minutes.2,2-Dimethyl-6-bromo-chroman-4-one is available in accordance with theprocedure of Bickle et al. J. Med. Chem. 1990 33 p3028. The reaction wasquenched with water (5 mL), extracted with ethyl acetate (10 mL), washedwith brine, dried and the solvent was removed by evaporation.Chromatography of the crude mixture afforded2,2-dimethyl-4-tolyl-4-hydoxy-6-bromo-chroman an oil. This product wasdissolved in dichloromethane (25 mL), and pTSA (25 mg) was added and themixture stirred for 12 hours. The mixture was then diluted with ethylacetate (125 mL), washed with 10% NaHCO₃ (10 mL), brine, dried and thesolvent was removed by evaporation to afford a the title compound as ayellow oil.

¹HNMR (CDCl₃): δ 1.48 (s, 6H), 2.41 (s, 3H), 5.61 (s, 1H), 6.76 (d,J=8.3 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.22 (s, 4H), 7.26 (dd, J=2.4,8.3 Hz, 1H).

2,2-Dimethyl-4(tol4-yl)-chrom-3-en-6-al (Compound Q)

To a cold (−78° C.) solution of2,2-dimethyl-4(tol-4-yl)-6-bromo-chrom-3-ene (Compound P, 480 mg, 1.45mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution, 1.1mL) and the mixture was stirred for 30 minutes. DMF (200 mg, 2.9 mmol)was added, the mixture was warmed to ambient temperature and stirred for3 hours. The reaction was diluted with ethyl acetate (150 mL), washedwith brine (10 mL), dried and the solvent was removed by evaporation.Purification by chromatography on silica gel column gave the titlecompound as a colorless oil.

¹HNMR (CDCl₃): δ 1.54 (s, 6H), 2.41 (s, 3H), 5.66 (s, 1H), 6.98 (d,J=8.3 Hz, 1H), 7.24 (s, 4H), 7.57 (d, J=2.0 Hz, 1H), 7.71 (dd, J=2.0,8.3 Hz, 1H), 9.77 (s, 1H).

Ethyl-4-[2,2-dimethyl-4-(tol4-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benzoate(Compound 9)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 1.4 g,3.6 mmol) in THF (9 mL) was added n-BuLi in hexane (1.6 M solution, 2.8mL). The mixture was gradually warmed to ambient temperature over 30minutes and stirred for 5 minutes. To this mixture was added2,2-dimethyl-4(tol-4-yl)-chrom-3-en-6-al (Compound Q, 260 mg, 0.93 mmol)in THF (1 mL) at ambient temperature and the mixture was stirred for 5hours. The reaction mixture was diluted with ethyl acetate (100 mL) andwashed with brine (10 mL) dried and the solvent was removed byevaporation. The residual material was subjected to flash chromatographyon silicagel to obtain the E and Z olefinic compounds, which weredissolved in dichloromethane (5 mL) and cooled to −50° C. A solution ofSnCl₄ in dichloromethane (150 mg in 0.7 mL) was added to the olefiniccompounds. The reaction mixture was gradually warmed to −10° C. over 3hours and then quenched with methanol and water. The reaction mixturewas diluted with ethyl acetate (100 mL). The organic layer was washedwith brine and dried. Solvent was removed under reduced pressure and theresidue purified by chromatography on silicagel to afford the titlecompound as a white solid.

¹HNMR (CDCl₃): δ 1.43 (t, J=7.1 Hz, 3H), 1.55 (s, 6H), 2.45 (s, 3H),4.41 (q, J=7.1 Hz, 2H), 5.85 (s, 1H), 7.24–7.38 (m, 5H), 7.53 (s, 1H),7.65–7.78 (m, 4H), 7.88 (s, 1H), 8.11 (d, J=8.5 Hz, 2H).

4-[2,2-Dimethyl-4-(tol-4-yl)-benzo(1,2-g)-chrom-3-en-7yl]benzoic acid(Compound 10)

By following the procedure employed for the preparation of4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoicacid (Compound 4), ethyl4-[2,2-dimethyl-4-(tol-4-yl)-benzo(1,2-g)-chrom-3-en-7-yl]benzoate(Compound 9, 10 mg, 0.02 mmol), was converted into the title compoundusing LiOH in water (0.2 mL, 0.2 mmol). The title compound was obtainedas an off white solid.

¹HNMR (Acetone-D6): d 1.52 (s, 6H), 2.41 (s, 3H), 5.96 (s, 1H),7.27–7.38 (m, 4H), 7.60 (s, 1H), 7.78–7.86 (m, 3H), 7.90 (d, J=8.2 Hz,2H), 8.10 (d, J=8.2 Hz, 2H), 8.11 (s, 1H).

2,2-Dimethyl-4(5-methyl-thien-2-yl)-6-bromo-chrom-3-ene (Compound R)

To a cold (−78° C.) solution of 2-methylthiophene (820 mg, 8.3 mmol) inTHF (16 mL) was added n-BuLi in hexane (1.6M, 4.4 mL, 8.5 mmol). Themixture was warmed to ambient temperature and stirred for 15 minutes.This solution was added to a flask containing cold (−78° C.) solution of2,2-dimethyl-6-bromo-chroman-4-one (1.08 g, 4.2 mmol) in THF (4 mL). Themixture was stirred and allowed to gradually warm to ambient temperatureover 8 hours, and then stirred for an additional 4 hours at ambienttemperature. The mixture was diluted with ethyl acetate (200 mL), washedwith 10% HCl, brine (20 mL), dried and the solvent was removed byevaporation. The product was purified by chromatography on a silica gelcolumn to afford the title compound as a colorless oil.

¹HNMR (CDCl₃): δ 1.46 (s, 6H), 2.52 (s, 3H), 5.75 (s, 1H), 6.73 (brs,1H), 6.76 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H), 7.26 (dd, J=2.5,8.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H).

2,2-Dimethyl-4(5-methyl-thien-2-yl)-chrom-3-en-6-al (Compound S)

To a cold (−78° C.) solution of2,2-dimethyl-4(5-methyl-thien-2-yl)-6-bromo-chrom-3-ene (Compound R, 1.2g, 3.6 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution,2.3 mL). After 30 minutes, DMF (465 mg, 5 mmol) was added and themixture was allowed to warm to ambient temperature and stirred for 3hours. The mixture was diluted with ethyl acetate (150 mL), washed withbrine (10 mL), dried and the solvent was removed by evaporation.Purification by chromatography on silica gel column gave the titlecompound as a colorless oil.

¹HNMR (CDCl₃): δ 1.51 (s,6H), 2.52 (s, 3H), 5.80 (s, 1H), 6.75 (d, J=2.7Hz, 1H), 6.91 (d, J=2.7 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 7.73 (dd,J=2.0, 8.3 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 9.83 (s, 1H).

Ethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benzo[1.2-g]-chrom-3-en-7-yl]benzoate(Compound 11)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 690 mg,1.75 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6 M solution, 1.1mL). The mixture was gradually warmed to ambient temperature over 30 minand stirred for 5 minutes. The mixture was recooled to −78° C. and2,2-dimethyl-4(5-methyl-thien-2-yl)-chrom-3-en-6-al (Compound S, 300 mg,1.1 mmol) in THF (1 mL) was added to the reaction mixture. The mixturewas stirred at ambient temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate (100 mL) and washed with brine (10 mL) driedand the solvent was removed by evaporation. The material was subjectedto flash chromatography on silica gel to obtain the E and Z olefiniccompounds, which were dissolved in dichloromethane (5 mL) and cooled to−78° C. A solution of SnCl₄ in dichloromethane (52 mg in 0.2 mL) wasadded to the olefinic compounds. The resulting mixture was stirred for30 minutes, quenched with methanol, water and diluted with ethyl acetate(100 mL). The organic layer was washed with brine and dried. Solvent wasremoved under reduced pressure and purified by silicagel chromatographyto afford the title compound as a white solid.

¹HNMR (CDCl₃): δ 1.43 (t, J=7.1 Hz, 3H), 1.53 (s, 6H), 2.56 (s, 3H),4.41 (q, J=7.1 Hz, 2H), 5.99 (s, 1H), 6.79 (d, J=3.5 Hz, 1H), 7.00 (d,J=3.5 Hz, 1H), 7.29 (s, 1H), 7.68 (dd, J=1.8, 8.5 Hz, 1H), 7.72–7.79 (m,3H), 7.93 (s, 1H), 7.97 (s, 1H), 8.14 (d, J=8.5 Hz, 2H).

4-[2,2-Dimethyl-4-(5-methyl-thien-2-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benzoicacid (Compound 12)

To a solution ofethyl-4-[2,2-dimethyl-4-(5-methyl-thien-2-yl)-benzo[1,2-g]-chrom-3-en-7-yl]benzoate(Compound 11, 18 mg, 0.03 mmol) in methanol (0.5 mL) and THF (1 mL), wasadded LiOH in water (1M solution, 0.3 mL). The reaction mixture wasstirred for 20 hours, the solvent was removed under reduced pressure,the residue dissolved in water (5 mL), washed with ether (10 mL) and theaqueous layer was acidified to PH 5. The aqueous layer was extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried, and the solvent was removed under reduced pressure toafford the title compound as a pale yellow solid.

¹HNMR (CH₃COCH₃): δ 1.50 (s, 6H), 2.52 (s, 3H), 6.11 (s, 1H), 6.85 (brs,1H), 7.07 (d, J=3.3 Hz, 1H), 7.31 (s, 1H), 7.80–7.90 (m, 2H), 7.91 (d,J=8.4, 2H), 8.01 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 8.19 (s, 1H).

2,2-Dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene (Compound T)

To a cold (−78° C.) solution of 2-methylthiophene (1.2 g, 12.2 mmol) inTHF (8 mL) was added n-BuLi in hexane (1.6M, 8.5 mL). The mixture waswarmed to ambient temperature over 30 minutes. with stirring. Themixture was recooled to −78° C. and a solution of2,2-dimethyl-6-bromo-thiochroman-4-one (Compound M, 1.4 g, 5.2 mmol) inTHF (10 mL) was added. The mixture was stirred for 16 hours at ambienttemperature. Then the reaction mixture was diluted with ether (125 mL),washed with water (10 mL), brine (10 mL) dried and the solvent wasremoved by evaporation. The product was seperated by columnchromatography and was dissolved in dichloromethane (5 mL). To thissolution p-TSA (5 mg) was added and the mixture was stirred at ambienttemperature for 5 min. The reaction was quenched with 10% NaHCO₃ (3 mL),washed with brine (5 mL), dried and the solvent was removed bydistillation. The residual crude material was purified by columnchromatography to obtain the title compound as a pale yellow oil.

¹HNMR (CDCl₃): d 1.44 (s, 6H), 2.51 (s, 3H), 6.00 (s, 1H), 6.72 (d,J=1.1 Hz, 1H), 6.79 (d, J=1.1 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.29 (dd,J=2.1, 8.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H).

2,2-Dimethyl-4(2-methyl-thien-5-yl)-thiochrom-3-en-6-al (Compound U)

To a cold (−78° C.) solution of2,2-dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene (Compound T,430 mg, 1.2 mmol) in THF (12 mL) was added n-BuLi in hexane (1.6 Msolution, 1 mL). The mixture was gradually warmed to ambient temperatureover 1 hour and recooled to −78° C. To this solution was added DMF (220mg, 3 mmol) and the mixture was stirred at ambient temperature for 16hours. The reaction was quenched by adding water (10 mL) and ethylacetate (100 mL). The organic layer was washed with brine (10 mL),dried and the solvent was removed by distillation to obtain the titlecompound as a pale yellow oil.

¹HNMR (CDCl₃): d 1.47 (s, 6H), 2.51 (s, 3H), 6.03 (s, 1H), 6.72 (d,J=2.5 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.68 (dd,J=1.7, 8.1 Hz, 1H), 7.95 (d, J=1.7 Hz, 1H), 9.88 (s, 1H).

Ethyl

4-[2,2-dimethyl-4-(2-methyl-thien-5-yl)-6,7-benzothiochrom-3-en-7-yl]benzoate (Compound 13)

To a cold (−78° C.) solution of ethyl4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 500 mg,1.29 mmol) in THF (2.5 mL) was added freshly prepared lithiumdiisopropylamide in THF(1.5 mmol). The mixture was allowed to warm to−5° C. over a period of 1 hour and 40 minutes. The reaction mixture wasrecooled to −78° C. and2,2-dimethyl-4(2-methyl-thien-5-yl)-thiochrom-3-en-6-al (Compound U, 180mg, 0.58 mmol) in THF (2 mL) was added. The reaction mixture wasgradually warmed to −10° C. over 2 hours. Then the reaction was quenchedby adding water (5 mL) and ethyl acetate (70 mL). The organic layer waswashed with brine (10 mL) dried and the solvent was removed bydistillation. The product E and Z isomers were isolated by columnchromatography. The required E (minor) isomer (45 mg) was dissolved indichloromethane (5 mL) and cooled to −78° C. To this solution SnCl₄ (110mg, 0.42 mmol) in dichloromethane (1 mL) was added dropwise, thereaction mixture was gradually warmed to −30° C. over 30 min. Thereaction was quenched by adding ethanol (0.5 mL), water (5 mL) and ethylacetate (75 mL). The organic layer was washed with brine (10 mL), driedand the solvent was removed by distillation. The title compound wasisolated as a white solid after column chromatography.

¹HNMR (CDCl₃) : d 1.43 (t, J=7.1 Hz, 3H), 1.55 (s, 6H), 2.55 (s, 3H),4.42 (q, J=7.1 HZ, 2H), 6.19 (s, 1H), 6.75 (d, J=1.9 Hz, 1H), 6.90 (d,J=1.9 Hz, 1H), 7.70–7.85 (m, 4H), 7.87 (s, 1H), 7.97 (s, 1H), 8.00 (s,1H), 8.12 (d, J=8.4 Hz, 2H).

4-[2,2-Dimethyl-4-(2-methyl-thien-5-yl)-benzo(1,2-g)-thiochrom-3-en-7-yl]benzoicacid (Compound 14)

To a degassed solution of ethyl4-[2,2-dimethyl-4-(2-methyl-thien-5-yl)-benzo(1,2-g)-thiochrom-3-en-7-yl]benzoate(Compound 13, 28 mg, 0.06 mmol), in THF (2 mL) and MeOH (1 mL) was addedLiOH (1M solution in water, 0.2 mL) and the mixture was stirred for 16hours. The reaction was acidified to pH 4 and extracted with ethylacetate (50 mL). The organic layer was washed with brine, dried and thesolvent was removed to afford the title compound as a pale yellow solid.

¹HNMR (CDCl₁) : d 1.52 (s, 6H), 2.55 (s, 3H), 6.19 (s, 1H), 6.74 (d,J=1.9 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 7.71–7.85 (m, 4H), 7.88 (s, 1H),7.97 (s, 1H), 8.00 (s, 1H), 8.12 (d, J=8.4 Hz, 2H).

1. A compound of the formula

wherein R₁ is independently H or alkyl of 1 to 6 carbons; R₂ is optionaland is defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; n is an integer of between 0and 2; o is an integer between 0 and 3; R₃ is hydrogen, lower alkyl of 1to 6 carbons, F, Cl, Br or I; R₄ is heteroaryl or (R₅)_(p)-heteroarylwhere the heteroaryl group is 5-membered or 6-membered and has 1 to 3heteroatoms selected from the group consisting of O, S, and N; p is aninteger having the values of 0–5; R₅ is F, Cl, Br, I, NO₂, N(R₈)₂,N(R₈)COR₈, N(R₈)CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈, C₁₋₁₀ alkyl,fluoro substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl having 1 to 3 doublebonds, C₂₋₁₀ alkynyl having 1 to 3 triple bonds, or a (trialkyl)silyl or(trialkyl)silyloxy group where the alkyl groups independently have 1 to6 carbons; A is (CH₂)_(q) where q is 0–5, C₃₋₆ branched alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl having 1 or 2 double bonds, or C₂₋₆ alkynylhaving 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉R₁₀, CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁,CHO, CH(OR₁₂)₂, CHOR₁₃O, COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)3;R₇ is C₁₋₅ alkyl, C₃₋₅ cycloalkyl, or C₂₋₅ alkenyl; R₈ is C₁₋₁₀ alkyl,C₁₋₁₀(trimethylsilyl)alkyl, or C₅₋₁₀ cycloalkyl; R₉ and R₁₀ areindependently hydrogen, C₁₋₁₀ alkyl, C₅₋₁₀ cycloalkyl, phenyl orR₁₂-phenyl; R₁₁ is C₁₋₆ alkyl, phenyl, or R₁₂-phenyl; R₁₂ is C₁₋₆ alkyl;and R₁₃ is divalent alkyl radical of 2–5 carbons.
 2. A compound of claim1 where R₂ is optional and is defined as lower alkyl of 1 to 6 carbons,F, CF₃, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons; R₃ is hydrogen, lower alkyl of1 to 6 carbons, or F; and R₅ is F, NO₂, N(R₈)₂, OR₈, CN, C₁₋₁₀ alkyl,fluoro substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl having 1 to 3 doublebonds, or C₂₋₁₀ alkynyl having 1 to 3 triple bonds.
 3. A compound ofclaim 2 where A is (CH₂)_(q) and B is COOH or a pharmaceuticallyacceptable salt thereof, COORO₈, or CONR₉R₁₀.
 4. A compound of claim 3which has no R₂ group, and where R₁ is methyl, R₃ is H, and q is
 0. 5. Acompound of claim 4 where B is COOH or a pharmaceutically acceptablesalt thereof, COOMe, or COOEt.
 6. A compound of claim 5 where R₄ isthienyl, pyridyl, (R₅)_(p)-thienyl, or (R₅)_(p)-pyridyl.
 7. A compoundof claim 6 where B is COOH or a pharmaceutically acceptable saltthereof, or COOEt.
 8. A compound of claim 7 where R₄ is5-methyl(2-thienyl).
 9. A compound of claim 7 where R₄6-methyl(3-pyridyl).